Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Re-expression of the death-signalling p75 neurotrophin receptor (p75NTR) is associated with injury and neurodegeneration in the adult nervous system. The induction of p75NTR expression in mature degenerating spinal motor neurons of humans and transgenic mice with amyotrophic lateral sclerosis (ALS) suggests a role of p75NTR in the progression of motor neuron disease (MND). In this study, we designed, synthesized and evaluated novel antisense peptide nucleic acid (PNA) constructs targeting p75NTR as a potential gene knockdown therapeutic strategy for ALS. An 11-mer antisense PNA directed at the initiation codon, but not downstream gene sequences, dose-dependently inhibited p75NTR expression and death-signalling by nerve growth factor (NGF) in Schwann cell cultures. Antisense phosphorothioate oligonucleotide (PS-ODN) sequences used for comparison failed to confer such inhibitory activity. Systemic intraperitoneal administration of this antisense PNA to mutant superoxide dismutase 1 (SOD1G93A) transgenic mice significantly delayed locomotor impairment and mortality compared with mice injected with nonsense or scrambled PNA sequences. Reductions in p75NTR expression and subsequent caspase-3 activation in spinal cords were consistent with increased survival in antisense PNA-treated mice. The uptake of fluorescent-labelled antisense PNA in the nervous system of transgenic mice was also confirmed. This study suggests that p75NTR may be a promising antisense target in the treatment of ALS.
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PMID:Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice. 1453 57

Mutant copper/zinc superoxide dismutase (SOD1)-overexpressing transgenic mice, a mouse model for familial amyotrophic lateral sclerosis (ALS), provides an excellent resource for developing novel therapies for ALS. Several observations suggest that mitochondria-dependent apoptotic signaling, including caspase-9 activation, may play an important role in mutant SOD1-related neurodegeneration. To elucidate the role of caspase-9 in ALS, we examined the effects of an inhibitor of X chromosome-linked inhibitor of apoptosis (XIAP), a mammalian inhibitor of caspase-3, -7 and -9, and p35, a baculoviral broad caspase inhibitor that does not inhibit caspase-9. When expressed in spinal motor neurons of mutant SOD1 mice using transgenic techniques, XIAP attenuated disease progression without delaying onset. In contrast, p35 delayed onset without slowing disease progression. Moreover, caspase-9 was activated in spinal motor neurons of human ALS subjects. These data strongly suggest that caspase-9 plays a crucial role in disease progression of ALS and constitutes a promising therapeutic target.
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PMID:The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. 1465 37

The significance of copper/zinc superoxide dismutase (SOD1) and neuronal nitric oxide synthase (nNOS) co-localization to neurofilamentous (NF) aggregates in amyotrophic lateral sclerosis (ALS) is unknown. In this study, we have used dissociated motor neurons from either C57BL/6 or mice that over-express the human low molecular weight neurofilament protein (hNFL+/+) to examine the relationship between NF aggregate formation, SOD1 and nNOS co-localization, and the regulation of NMDA-mediated calcium influx in vitro. The intracellular distribution of NF aggregates, SOD1 and nNOS was examined by confocal microscopy and NMDA-induced alterations in intracellular calcium levels using either Oregon green fluorescence or FURA-2 photometric imaging. Cell death was assessed using an antibody to activated caspase-3. C57 Bl/6 motor neurons expressed nNOS in a punctate manner, whereas SOD1 was distributed homogeneously throughout the cytosol. In contrast, hNFL+/+ motor neurons demonstrated co-localization of SOD1 and nNOS by day 9 post-plating, preceding the formation of NF aggregates. Both proteins co-localized to NF aggregates once formed. With NMDA stimulation, aggregate-bearing hNFL+/+ motor neurons demonstrated significant increases in intracellular calcium, whereas only a minimal alteration in intracellular calcium was observed in C57 Bl/6 neurons. Following stimulation with 100 microM NMDA, 75.5+/-5.5% of hNFL+/+ neurons became apoptotic, whereas only 16.3+/-5.3% of C57 Bl/6 were. These observations suggest that the presence of NF aggregates results in a failure of regulation of NMDA-mediated calcium influx, and that this occurs due to the sequestration of nNOS to the NF aggregate, preventing its down-regulation of the NMDA receptor.
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PMID:Sequestration of nNOS in neurofilamentous aggregate bearing neurons in vitro leads to enhanced NMDA-mediated calcium influx. 1503 15

Insulin-like growth factor I (IGF-I) is currently in clinical trials for treatment of amyotrophic lateral sclerosis (ALS), but little is known about how it promotes the survival of motor neurons. In the current study, we examined IGF-I-mediated neuroprotection in an in vitro model of ALS utilizing enriched cultures of embryonic rat spinal cord motor neurons. IGF-I binds to the IGF-I receptor (IGF-IR) in motor neurons and activates MAPK and the downstream effector of phosphatidylinositol 3-kinase (PI-3K) signaling, Akt. IGF-I:IGF-IR signaling involves phosphorylation of IRS-1 and Shc, but not IRS-2. Glutamate, which is elevated in the cerebrospinal fluid of ALS patients, induced DNA fragmentation and caspase-3 cleavage in the spinal cord motor neurons. These effects of glutamate were blocked by co-treatment with IGF-I. However, a delay of IGF-I treatment for as little as 30 min eliminated its neuroprotective effect. Finally, alone, neither the MAPK pathway inhibitor PD98059 nor the PI-3K inhibitor LY294002 blocked the neuroprotective effect of IGF-I, but both inhibitors together were effective in this regard. These results suggest that the dose and timing of IGF-I administration are critical for producing a neuroprotective effect, and also suggest that both the MAPK and PI-3K/Akt pathways can promote the survival of motor neurons. We discuss our results in terms of novel strategies for ALS therapy.
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PMID:IGF-I prevents glutamate-induced motor neuron programmed cell death. 1519 97

Mutations in the gene coding for the ubiquitous, anti-oxidant enzyme Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), a fatal disease characterized by selective loss of motor neurons. Expression of a mutant SOD1 typical of fALS patients restricted to either motor neurons or astrocytes is insufficient to generate a pathological phenotype in mouse models, suggesting that a deleterious interplay between different cell types is necessary for the pathogenesis of the disease. In this study, we demonstrate the actual role of a functional cross-talk between glial and neuronal cells expressing fALS mutant G93A-SOD1, where an increase in the production of reactive oxygen species occurs. We show that human glioblastoma cells expressing G93A-SOD1 induce activation of caspase-1, release of cytokines, and activation of apoptotic pathways in cocultured human neuroblastoma cells also expressing G93A-SOD1. Activation of caspase-1 and caspase-3 is observed also in neuroblastoma lines expressing other fALS-SOD1s (G37R, G85R, and I113T) cocultured with glioblastoma lines expressing the corresponding mutant enzymes. These effects are consequent to activation of inflammatory processes in G93A-glioblastoma cells stimulated by cocultured G93A-neuroblastoma. Furthermore, selective death of embryonal spinal motor neurons from G93A-SOD1 transgenic mice is induced by coculture with G93A-glioblastoma and prevented by inhibition of NO synthase. Proinflammatory cytokines, interferon-gamma, and nitric oxide are among the molecular signals exchanged between glial and neuronal cells that generate a functional interplay between the two cell types. This cross-talk may be crucial for the pathogenesis of SOD1-linked fALS but also for the more common sporadic form of the disease, where markers of increased oxidative stress and of glial activation have been found.
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PMID:Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells. 1520 63

Creatine mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and traumatic brain injury. Because caspase-mediated pathways are shared functional mechanistic components in these diseases, as well as in ischemia, we evaluated the effect of creatine supplementation on an experimental stroke model. Oral creatine administration resulted in a remarkable reduction in ischemic brain infarction and neuroprotection after cerebral ischemia in mice. Postischemic caspase-3 activation and cytochrome c release were significantly reduced in creatine-treated mice. Creatine administration buffered ischemia-mediated cerebral ATP depletion. These data provide the first direct correlation between the preservation of bioenergetic cellular status and the inhibition of activation of caspase cell-death pathways in vivo. An alternative explanation to our findings is that creatine is neuroprotective through other mechanisms that are independent of mitochondrial cell-death pathways, and therefore postischemic ATP preservation is the result of tissue sparing. Given its safety record, creatine might be considered as a novel therapeutic agent for inhibition of ischemic brain injury in humans. Prophylactic creatine supplementation, similar to what is recommended for an agent such as aspirin, may be considered for patients in high stroke-risk categories.
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PMID:Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. 1522 38

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motoneurons in the spinal cord and brain stem. We have characterized motoneuron death in transgenic mice carrying the mutant human copper/zinc superoxide dismutase, as a model for familial ALS. Previous studies have shown the involvement of mitochondria in nerve cell demise in these animals. We report here an early cleavage of caspase-12, residing in the endoplasmic reticulum (ER), in the spinal cord during the course of the disease. Apart from caspase-12, caspase-9, and caspase-3 were activated in the transgenic ALS mice. Staining with an antibody for nitrotyrosine, as a marker for oxidative stress, showed a large increase in the ALS mice. The results indicate that oxidative and ER induced stress causing caspase-12 activation are involved in neuronal death and disease progression in ALS. Caspase-12 and the ER pathway for cell death may constitute potential novel targets for the treatment of ALS.
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PMID:Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS. 1531 3

The identification of the pathogenic mechanism of selective motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) may lead to the development of new therapies to halt or slow the disease course. A novel, MN-specific, Fas-mediated programmed cell death (PCD) pathway has been reported in MNs which involves the activation of p38 MAP kinase (phospho-p38) and neuronal nitric oxide synthase (nNOS). PCD was found to be exacerbated in MNs expressing ALS-linked superoxide dismutase (SOD) mutations. Because this MN-specific pathway was investigated in vitro, we performed an in vivo study to evaluate its potential involvement in MN loss in the lumbar region of spinal cord of mutant SOD transgenic (G93A) mice. Compared to nontransgenic littermates, we found significant increases in the numbers of immunopositive ventral horn MNs of G93A mice as young as 60 days of age for several constituents of this putative PCD pathway, including phospho-p38, nNOS, phospho-ASK1 MAP kinase kinase, and active caspase-3. This study provides in vivo evidence of an MN-specific PCD pathway that may be a pathogenic mechanism of ALS and may be activated very early in the disease process, well before clinical symptoms are evident (200 days). These findings suggest that early diagnosis and therapeutic intervention may be critical for the successful treatment of the disease. These enzymes may provide new markers for earlier diagnosis of ALS and new molecular targets for therapeutic intervention.
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PMID:Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model. 1549 59

Age-dependent poliomyelitis (ADPM) or murine amyotrophic lateral sclerosis (ALS) is a murine paralytic disease triggered in immunosuppressed genetically-susceptible mice by infection with the arterivirus lactate dehydrogenase-elevating virus (LDV). This disease provides an animal model for ALS, affecting anterior horn neurons and resulting in neuroparalysis 2-3 weeks after LDV infection. We have tested the hypothesis that spinal cord apoptosis is a feature of the LDV-induced murine ALS, since apoptosis is postulated to be a causal factor in human ALS. Gene microarray analyses of spinal cords from paralyzed animals revealed upregulation of several genes associated with apoptosis. Spinal cord apoptosis was investigated further by TUNEL and activated caspase-3 assays, and was observed to emerge concurrent with paralytic symptoms in both neuronal and non-neuronal cells. Caspase-3-dependent apoptosis was also triggered in cultured macrophages by neurovirulent LDV infection. Thus, virus-induced spinal cord apoptosis is a pre-mortem feature of ADPM, which affects both neuronal and support cells, and may contribute to the pathogenesis of this ALS-like disease.
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PMID:Lactate dehydrogenase-elevating virus induces apoptosis in cultured macrophages and in spinal cords of C58 mice coincident with onset of murine amyotrophic lateral sclerosis. 1552 45

Evidence from human amyotrophic lateral sclerosis (ALS) patients and ALS-linked Cu/Zn superoxide dismutase (Cu/Zn-SOD) transgenic mice bearing the mutation of glycine to alanine at position 93 (G93A) suggests that the pro-apoptotic protein prostate apoptosis response-4 (Par-4) might be a critical link in the chain of events leading to motor neuron degeneration. We now report that Par-4 is enriched in synaptosomes and post-synaptic density from the ventral horn of the spinal cord. Levels of Par-4 in synaptic compartments increased significantly during rapid and slow declining stages of muscle strength in hSOD1 G93A mutant mice. In the pre-muscle weakness stage, hSOD1 G93A mutation sensitized synaptosomes from the ventral horn of the spinal cord to increased levels of Par-4 expression following excitotoxic and apoptotic insults. In ventral spinal synaptosomes, Par-4-mediated production of pro-apoptotic cytosolic factor(s) was significantly enhanced by the hSOD1 G93A mutation. RNA interference (RNAi) knockdown of Par-4 inhibited mitochondrial dysfunction and caspase-3 activation induced by G93A mutation in synaptosomes from the ventral horn of the spinal cord, and protected spinal motor neurons from apoptosis. These results identify the synapse as a crucial cellular site for the cell death promoting actions of Par-4 in motor neurons, and suggest that targeted inhibition of Par-4 by RNAi may prove to be a neuroprotective strategy for motor neuron degeneration.
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PMID:RNAi knockdown of Par-4 inhibits neurosynaptic degeneration in ALS-linked mice. 1560 96


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